Calcium receptors sense extracellular Ca2+ concentration and increase intracellular Ca2+, thereby suppressing the production of parathyroid hormone (PTH) involved in the control of Ca2+ metabolism and bone metabolism.
The serum calcium concentration of healthy mammal is strictly maintained at about 9-10 mg/100 ml (ca. 2.5 mM), which is referred to as calcium homeostasis of living organisms. When this value falls to not more than 50%, tetania occurs, and when it increases by 50%, consciousness is clouded, both cases threatening the lives. For maintaining calcium homeostasis, duodenum acts as a Ca2+ uptake organ, bone acts as a Ca2+ storage organ, and kidney acts as a Ca2+ excretory organ. These Ca2+ kinetics are controlled by various hormones generally referred to as “calcium controlling hormone”. Representative hormone includes active vitamin D [1α, 25(OH)2D3], PTH, calcitonin, Parathyroid Hormone-Related Protein (PTH-related Protein (PTHrP)) and the like.
Bone plays an important role not only as a supporting framework and motor organ of the body, but also as a storage organ of Ca2+, which is its constituent component. To fulfill such functions, bone tissues repeat formation thereof (osteogenesis) and absorption thereof (bone resorption) throughout the entire life. For osteogenesis, osteoblast derived from mesenchymal cell plays a major role, and for bone resorption, osteoclast derived from hematopoietic cell plays a major role. Osteogenesis is a mechanism including osteoid formation by bone organic matrix (bone matrix proteins such as type I collagen and the like) produced by osteoblast present on the osteogenesis surface, and subsequent calcification. Bone resorption is a mechanism including adhesion of osteoclast to the bone surface, intracellular absorption of Ca2+ via acid secretion and ion transport, and excretion of absorbed Ca2+ to the bone marrow side, thereby releasing Ca2+ into blood. The deficient part of the bone absorbed by osteoclast is repaired by osteogenesis by osteoblast. This series of phenomena are called remodeling of bone, and by the remodeling, old bones are replaced by new bones, thus maintaining the strength of the entire bone while maintaining calcium homeostasis.
PTH is a hormone that plays a key role in maintaining the calcium homeostasis. When blood Ca2+ concentration decreases, secretion of PTH from the parathyroid gland is promoted immediately, which, in the bone, acts on osteoblast (activation of osteoclast by osteoblast, production of bone organic matrix decomposition enzyme and the like) to promote osteoclastic bone resorption, whereby Ca2+ is transferred from the bone into the blood. In kidney, PTH promotes resorption of Ca2+ in the distal convulted tubule, and activates 25(OH) vitamin D3 in the proximal tubule, thereby promoting the production of active vitamin D3 [1α, 25(OH)2D3] having a function of promoting resorption of Ca2+ from the intestine. It also suppresses resorption of phosphorus As mentioned above, PTH directly or indirectly increases blood Ca2+ concentration.
When blood Ca2+ concentration increases, calcium receptor senses it, immediately suppresses secretion of PTH from the parathyroid gland to decrease the amount of Ca2+ to be supplied into the blood [Brown, E. M., Homeostatic mechanisms regulating extracellular and intracellular calcium metabolism, in the parathyroids, p.19, (1994), Raven press, New York]. Secretion of PTH is also suppressed by active vitamin D [1α, 25(OH)2D3].
Because PTH is a hormone assuming an important role in controlling Ca2+ metabolism and bone metabolism, attempts have been made to apply PTH to the treatment of osteoporosis. In 1982, Tam et al. found that sustained administration of bovine PTH (1-84) to thyroid/parathyroid gland enucleated rat results in promotion of both osteogenesis and bone resorption of femoral cancellous bone, leading to a decrease in net bone mass, but subcutaneous intermittent administration thereof does not result in promotion of bone resorption but in promotion of osteogenesis alone, leading to an increase in the bone mass [Endocrinology, 110, 506-512 (1982)]. Furthermore, Uzawa et al. compared the actions of sustained administration and intermittent administration of PTH with regard to epiphysial long bone and metaphysial cancellous bone of young rat. As a result, they clarified that sustained-administration of PTH results in remarkable increase in bone mass in metaphysial cancellous bone highly susceptible to the effect of enchondral ossification, though associated with abnormal findings such as hyperplasia of epiphysial plate cartilage, fibrous ostitis and the like, and in marked promotion of bone resorption and decrease in bone mass accompanied by rarefaction of cortical bone, in epiphysial cancellous bone where the effect is small [Bone, 16, 477-484 (1995)]. In addition, it has been reported that intermittent administration of PTH results in significant increases in bone mass and bone trabecula in both epiphysial and metaphysial cancellous bones without increase in osteoclast or decrease of cortical bone.
Moreover, Scutt et al. have reported that, in chicken calvaria derived osteoblast, a short time (10-20 min) treatment with PTH promotes cell growth as compared to a long time (18 hr) treatment [Calcif. Tissue Int., 55, 208-215 (1994)]. This suggests that some of the actions of PTH on osteoblast are temporary and that expression of the action by the treatment for an extremely short time may be related to the fact that sustained administration and intermittent administration of PTH in vivo show different actions on bone tissues.
Ishizuya et al. further clarified through investigation of the action of PTH on differentiation of osteoblast using an in vitro experiment system that the action of PTH varies depending on the treatment time. They have reported that sustained action of PTH on osteoblast derived from rat calvaria resulted in strong inhibition of differentiation of osteoblast and nearly complete inhibition of osteogenesis in vitro, but repeated PTH action for the first 6 hr of 48 hr as one cycle resulted in significant promotion of differentiation of osteoblast and promotion of osteogenesis in vitro.
PTH is considered to not only prevent decrease in bone mass of osteoporosis model, but also has a bone mass recovery effect even on an animal already suffering from marked decrease in bone mass. Wronski et al. intermittently administered human PTH (1-34) to 90-day-old SD rat at 4 weeks post-ovariectomy and showing an obvious decrease in cancellous bone, for 15 weeks from 4 weeks post-ovariectomy. As a result, promotion of osteogenesis and inhibition of bone resorption were observed during the period of from week 5 to week 10 after the start of the administration, showing increased bone mass of about twice the bone mass of sham operation group [Endocrinology, 132, 823-831 (1993)]. They have also reported that, in this experiment, estrogen and bisphosphonate prevented decrease in bone mass caused by ovariectomy but did not show increase in bone mass, unlike PTH. They detailedly analyzed the cortical bone of this experiment system and found images showing promoted osteogenesis and bone mass increase on the periost side and endosteum side by intermittent administration of human PTH (1-34), based on which they have clarified that the increase in cancellous bone due to PTH did not accompany decrease in cortical bone [Bone, 15, 51-58 (1994)].
Furthermore, Mosekilde et al. have reported that intermittent administration of human PTH (1-34) or human PTH (1-84) causes not only an increase in bone mass but also a dose-dependent increase in compression strength and bending strength, which are indices of bone substance, of cancellous bone [Endocrinology, 129, 421-428 (1991)] and cortical bone [J. Bone Miner. Res., 8, 1097-1101 (1993)] of rat vertebral bone. As discussed above, since PTH shows an obvious bone mass increasing action in experimental animals, various investigations are ongoing as regards the restrictive conditions expected in actual clinical applications. Mizoguchi studied whether or not a pharmacological effect is observed by intermittent administration of PTH, even when PTH in blood, which is considered to be one of the factors responsible for osteoporosis, has significantly increased, and concluded that the bone mass increased as usual [Journal of Japanese Society of Bone Morphometry, vol. 5, pp. 33-39 (1995)]. Takao et al. have studied the frequency of PTH administration and reported that administration of once a week for 12 weeks to healthy rat scarcely promoted bone absorption but dose-dependently increased the bone mass [Japanese Journal of Bone Metabolism, vol. 12 (Suppl.), p. S343 (1994)], suggesting possible effectiveness of clinically useful low frequency administration. The foregoing achievements suggest the possibility of PTH for making a potent and promising therapeutic drug for the treatment of postmenopausal osteoporosis or postovariectomy osteoporosis, which increases bone mass and decreases bone fracture rate.
These results clearly indicate that intermittent administration of PTH would enable treatment of osteoporosis. On the other hand, PTH problematically requires injection as an administration route, which is painful for many patients. However, an orally administrable pharmaceutical agent that can intermittently increase PTH concentration in blood is greatly expected to become a therapeutic drug of osteoporosis, which is based on a new action mechanism different from that of the above-mentioned PTH and conventional calcitonin.
Calcium receptor is a G protein coupled receptor, which is cloned as a molecule essential for controlling PTH secretion, and which penetrates cell membrane 7 times. Human calcium receptor consists of 1078 amino acids, and shows 93% amino acid homology with bovine calcium receptor. Human calcium receptor consists of a large N terminal extracellular region consisting of 612 amino acids, a cell membrane penetration region consisting of 250 amino acids and a C terminal intracellular region consisting of 216 amino acids.
Expression of calcium receptor has been found in parathyroid gland, kidney, thyroid C cell, brain and the like, as well as in bone (bone marrow cells).
When calcium receptor is bound with a ligand such as Ca2+ and the like, it activates phospholipase C in conjugation with G protein, causes production of inositol triphosphate and increase in intracellular Ca2+ concentration, and as a result, suppresses secretion of PTH [Nature, 366, 575-580 (1993)].
As mentioned above, a pharmaceutical agent that inhibits activation of calcium receptor, or a pharmaceutical agent that antagonizes calcium receptor, removes suppression of PTH secretion in parathyroid gland cells, and promotes secretion of PTH. If the antagonistic action can increase blood PTH concentration discontinuously and intermittently, its antagonist is expected to show the same effect as provided by intermittent administration of PTH, and a pharmaceutical agent extremely effective for the treatment of osteoporosis is considered to be provided.
As a CaSR antagonist, international publication WO99/51569 describes a compound of the following formula wherein    Y1 is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C1-4 alkyl, or O;    Y2 is methylene, unsubstituted or substituted by C1-4 alkyl or haloalkyl;    Y3 is a covalent bond or O, S, N—RIV or C1-4 alkylene-O, C1-4 alkylene-S, C1-4 alkylene-N—RIV;    R3 and R4 are, independently, methyl or ethyl, or, together, form cyclopropyl;    R5 is aryl or fused aryl, dihydro or tetrahydro fused aryl, unsubstituted or substituted with any substituents being selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3, CH2CF3, (CH2)nCO2RIV, and O—(CH2)nCO2RIV, wherein n is an integer from 0 to 3 and RIV is selected from the group consisting of H, C1-4 alkyl, and C3-6 cycloalkyl;    or R5 is heteroaryl or fused heteroaryl; wherein the hetero-ring contains N, O or S, and is aromatic, dihydro or tetrahydro, unsubstituted or substituted with any substituents being selected from the group consisting of OH, OCH3, CH(CH3)2, halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3, CH2CF3, (CH2)nCO2H, (CH2)nCO2RIV, and O—(CH2)nCO2RIV;    G is a covalent bond, CHR6 or C—R6, wherein R6 is H, OH or O (forming a ketone);    R7 is H, OH, or O—C1-4 alkyl;    R8 is H or C1-4 alkyl; or R7 and R8 together form a ketone;    A and B are, independently, selected from the group consisting of a bond, CH2, NH, O, S and C═O, provided that A or B is selected from CH2 and NH; or A and B together form a bond; or the A-B moiety is represented by CH═CH or C≡C;wherein    X1 and X5 are independently selected from the group consisting of H, halogen, CN, NO2, C1-4 alkyl, cycloalkyl, CH2-aryl, and CH2-heteroaryl; provided that either X1 or X5 is H;    X2, X3 and X4 are selected from the group consisting of H, halogen, O—C1-4 alkyl, O-aryl, O-heteroaryl, CH2-aryl, CH2-heteroaryl, alkyl, C(O)aryl, C(O)heteroaryl CH(OH)aryl, CH(OH)heteroaryl and J-K;    J is a covalent bond, alkylene, O-alkylene or alkenylene of up to 5 carbon atoms, unsubstituted or substituted by a substituent selected from the group consisting of C1-4 alkyl, OH, O(forming a ketone), aryl, heteroaryl, and NR′R″, wherein R′ and R″ are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, C(O)alkyl, C(O)aryl, and C(O)heteroaryl;    K is selected from the group consisting of CO2RIV, OH, and CN; and pharmaceutically acceptable salts and complexes thereof.
Particularly, a compound of the formula wherein Y3 is C1-4 alkylene-O is suggested, though not directly described. In this case, however, “C1-4 alkylene” means a straight chain, and the branched chain such as in the present invention is not described or suggested.
In addition, international publication WO99/51241 describes, as a CaSR antagonist, a compound of the following formula wherein    Y1 is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C1-4 alkyl or O;    Y2 is methylene, unsubstituted or substituted by C1-4 alkyl or haloalkyl;    Y3 is covalent bond or selected from the group consisting of O, S, N—RIV, C1-4 alkylene-O, C1-4 alkylene-S, and C1-4 alkylene-N—RIV;    IV is selected from the group consisting of H, C1-4 alkyl, and C3-6 cycloalkyl;    R3 and R4 are, independently, methyl or ethyl, or, together, form cyclopropyl;    R5 is heteroaryl or fused heteroaryl; wherein the hetero-ring contains N, O or S, and is aromatic, dihydro or tetrahydro, unsubstituted or substituted with any substituents being selected from the group consisting of OH, OCH3, CH(CH3)2, halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3, CH2CF3, (CH2)nCO2H, (CH2)nCO2RIV, and O—(CH2)nCO2RIV;    n is an integer of from 0 to 3;    G is a covalent bond, CHR6 or C—R6, wherein R6 is H, OH or O (forming a ketone);    R7 is H, OH, or O—C1-4 alkyl;    R8 is H or C1-4 alkyl; or R7 and R8 together form a ketone;    A and B are, independently, selected from the group consisting of a bond, CH2, NH, O, S and C═O, provided that either A or B is selected from CH2 and NH; or A and B together form a bond;    or A-B moiety is represented by CH═CH or C≡C;    X is selected from sub formulas (Ia) to (Ie) hereinbelow: wherein    W is selected from the group consisting of R1, SO2R1, C(O)R1, SO2NR1R1′, C(O)NR1R1′, C(O)OR1, and SO3R1′, wherein R1 and R1′ are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl, aryl and aryl C1-4 alkyl; or R1 and R1′ together form a 3 to 7 membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R, CO2NHR, OH, OR, NH2, halo, CF3, OCF3 and NO2; wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X1 is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ represents C1-4 alkyl, or C3-6 cycloalkyl;    X2, X3 and X4 are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3 and OSO2R″, provided that either X1 or X3 is H, wherein R″ is C1-4 alkyl or haloalkyl; or X1 and X2 together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C1-4 alkyl,    OCF3, CF3, OMe, CN, OSO2R′ and NO2; or X3 and X4 independently represent C(O)R1; and    R2 is selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl, aryl and aryl-C1-4 alkyl;    X1″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″, X3″ and X4″ are, independently, selected from the group consisting of CN, NO2, CO, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, provided that either X1″ or X3″ is H, wherein R′ is C1-4 alkyl or haloalkyl; or X1″ and X2″ together form an aryl or heteroaryl ring, substituted or unsubstituted, wherein the heteroatom is selected from N, S and O and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3″ and X4″ independently represent C(O)R1; and    R1″ and R2″ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1″ and R2″ together form a 3 to 7 membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2;wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;    X1′″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2′″, X3′″ and X4′″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, provided that either X1′″ or X3′″ is H, wherein R′ is C1-4 alkyl or haloalkyl;    or X1′″ and X2′″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1-4 alkyl OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3′″ and X4′″ independently represent C(O)R1;    R1′″ and R2′″ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1′″ and R2′″ together form a 3 to 7 membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;    D is selected from the group consisting of H, CN, NO2, Cl, F, Br, I, R, OR, SR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, C3-6 cycloalkyl, or C1-10 aryl or heteroaryl wherein the heteroatom is selected from N, S and O and substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    n is the integer of 1 or 2;    each E is independently C or N, provided that less than two E moieties is N; further provided that when n is 2, each E is C;    a and b are optionally present bonds;    R1IV is selected from the group consisting of (CH2)nCO2R′, (CH2)nCO2H, (CH2)nCONR′2, (CH2)nCH2OR′, OR′, SR′, CN, NO2, Cl, F, BR, I, H, CF3, OCF3, OSO2R′, R′ and H; wherein R′ is C1-4 alkyl, or C3-6 cycloalkyl;    or R1IV is O, forming a ketone such that YR1IV represents —C═O;    R2IV is selected from the group consisting of hydrogen, CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3, and OSO2R″; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl.    Y is selected from the group consisting of C, CH, O, N and S;    provided that when Y is S, R1IV is O or not present; further provided that when Y is O, R1IV is not present;    X′ is CH2, NH, O and S.    R9 is O-alkyl, O—CH2-aryl, and O-aryl;    X1″″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″″, X3″″, and X4″″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, provided that either X″″1 or X″″3 is H, wherein R′ is C1-4 alkyl or haloalkyl;    or X1″″ and X2″″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3″″ and X4″″ independently represent C(O)R1:and pharmaceutically acceptable salts and complex thereof.
Again, a compound of the formula wherein Y3 is C1-4 alkylene-O is suggested, though not directly described. In this case, however, “C1-4 alkylene” means a straight chain, and the branched chain such as in the present invention is not described or suggested.
International publication WO98/45255 (EP-A-973730) also describes a compound of the following formula as a CaSR antagonist wherein    Y1 is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C1-4 alkyl;    Y2 is methylene, unsubstituted or substituted by C1-4 alkyl or CF3;    Z is selected from the group consisting of a covalent bond, O, S, NH, N—C1-4 alkyl, O(CH2)n, (CH2)nO, NR′″C═O and C═ONR′″, where R′″ is C1-4 alkyl and n is an integer from 1 to 3, R3 and R4 are, independently, methyl or ethyl, or, together, form cyclopropyl;    R5 is phenyl or naphthyl, unsubstituted or substituted with one or more substituents selected from the group consisting of OH, C1-4 alkyl CH(CH3)2, halo, halo C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3 and CH2CF3, wherein RIV represents C1-4 alkyl or C3-6 cycloalkyl;    G is a covalent bond or C—R6 wherein R6 is H, OH or O (forming a carbonyl moiety);    R7 is H, OH, or O—C1-4 alkyl;    R8 is H or C1-4 alkyl; or R7 and R8 together form a carbonyl moiety;    the A-B moiety is represented by CH2CH2, a covalent bond, —CH═CH— or —C≡C—; and    X is selected from the group consisting of sub formulae (Ia), (Ib), (Ic), (Id) and (Ie) hereinbelow: whereinin sub formula (Ia):    W is selected from the group consisting of R1, SO2R1, C(O)R1, SO2NR1R1′, C(O)NR1R1′ and C(O)OR1SO3R1′, wherein R1 and R1′ are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl aryl and aryl C1-4 alkyl; or R1 and R1′ together form a 3- to 7-membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R, CO2NHR, OH, OR, NH2, halo, CF3, OCF3 and NO2; wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X1 is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ represents C1-4 alkyl, or C3-6 cycloalkyl;    X2, X3 and X4 are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3 and OSO2R″, wherein R″ is C1-4 alkyl or haloalkyl; or X1 and X2 together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2R′ and NO2; or X3 and X4 independently represent C(O)R1;    provided that when there are multiple halo substitutions in the haloalkyl, halo represents F; also provide that either X1 or X3 is hydrogen; and    R2 is selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl aryl and aryl-C1-4 alkyl;in sub formula (Ib):    X1″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″, X3″ and X4″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ is C1-4 alkyl or haloalkyl; provided that when there are multiple halo substitutions in the haloalkyl, halo represents F, or X1″ and X2″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected form N, S and O and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3″ and X4″ independently represent C(O)R1;    provided that either X1″ or X3″ is hydrogen; and    R1″ and R2″ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1″ and R2″ together form a 3 to 7 membered optionally substituted heterocyclic ring; optionally containing an additional heteroatom selected from O, S and N; wherein any substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;in sub formula (Ic):    X1′″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2′″, X3′″ and X4′″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ is C1-4 alkyl or haloalkyl; provided that when there are multiple halo substitutions in the haloalkyl, halo represents F; or X1′″ and X2′″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2; or    X3′″ and X4′″ independently represent C(O)R1;    provided that either X1′″ or X3′″ represents H; and    R1′″ and R2′″ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1′″ and R2′″ together form a 3 to 7 membered optionally substituted heterocyclic ring optionally containing an additional heteroatom selected from O, S and N; wherein the substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;in sub formula (Id):    D is selected from the group consisting of CN, NO2, Cl, F, Br, I, R, OR, SR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, C3-6 cycloalkyl, or C1-10 aryl or heteroaryl wherein the heteroatom is selected from N, S and O and substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    n is the integer of 1 or 2;    each E is independently C or N, provided that no more than two E moieties are N;    further provided that when n is 2, each E is C;    a and b are optionally present bond;    R1IV is selected from the group consisting of (CH2)nCO2R′, (CH2)nCO2H, (CH2)nCONR′2, (CH2)nCH2OR′, OR′, SR′, CN, NO2, Cl, F, Br, I, CF3, OCF3, OSO2R′, R′ and H; wherein R′ is C1-4 alkyl, or C3-6 cycloalkyl;    or R1IV is O forming a ketone such that YR1IV represents —C═O;    R2IV is selected from the group consisting of hydrogen, CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3, and OSO2R″; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl.    Y is selected from C, CH, O, N and S; provided that when Y is S, R1IV is O; further provided that when Y is O, R1IV is not present;    X′ is CH2, NH, O and S; and    attachment is at the carbon atom marked 3;in sub formula (Ie):    X1″″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″″, X3″″ and X4″″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3 and OSO2R″, wherein R″ is C1-4 alkyl or haloalkyl; or X1″″ and X2″″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2R′ and NO2; or X3″″ and X4″″ independently represent C(O)R1;    provided that when there are multiple halo substitutions in the haloalkyl, halo represents F; also provided that either X1″″ or X3″″ is hydrogen;    and R9 is O—CH2-alkyl, O—CH2-aryl and O-aryl.
In addition, Japanese Patent Application under PCT laid-open under kohyo No. 2001-501584 (WO97/37967, EP-A-901459, U.S. Pat. No. 6,022,894) also describes a compound of the following formula as a CaSR antagonist. wherein    R1 is selected from the group consisting of aryl, longer-length alk, and cycloalk;    R2 is selected from the group consisting of lower alk, cycloalk, alkoxy, H, OH, ═O, C(O)OH, C(O)O-lower alk, C(O)NH-lower alk, C(O)N(lower alk)2, SH, S-lower alk, NH2, NH-lower alk, and N(lower alk)2;    R3 and R4 is each independently lower alk or together cyclopropyl;    R5 is either an optionally substituted naphthyl having 1-4 substituents independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, Cl, F, Br, and lower haloalkoxy, or a substituted phenyl having 1-4 substituents with at least one substituent in a meta or para position selected from the group consisting of lower alkyl, methoxy, Cl, F, Br, and lower haloalkoxy, provided that said substituted phenyl may also have 2 or 3 additional substituents;    R6 if present is either hydrogen, lower alkyl or lower alkenyl, wherein R6 is not present if R2 is ═O;    Y1 is either a covalent bond, alkylene or alkenylene;    Y2 is alkylene;    Y3 is alkylene; and    Z is selected from the group consisting of a covalent bond, O, S, NH, N-lower alk, alkylene, alkenylene, and alkynylene, provided that if Z is O, S, NH, or N-lower alk, then Y1 is not a covalent bond; further provided that Y1 and Z may together form a covalent bond;    provided that R1 is not 6-CN-2-pyridyl;    further provided that if R5 is 3,4-dimethoxy-phenyl, then R1 is not CH3(CH2)5O-phenyl; 2-cyclopentyl-phenyl; 2-Cl-phenyl; 2-CN-phenyl; 2-(3-furanyl)phenyl; or 4-(1,2-benzisothiazole);    further provided that if R5 is 4-methoxy-phenyl, then R1 is not 2-cyclopentyl-phenyl; 2-CH3-phenyl; 2-benzyl-phenyl; 3-CH3, 4-CH3SO2-phenyl; 4-(1,2-benzisothiazole);    further provided that if R5 is 4-Cl-phenyl, then R1 is not 2-CH3-phenyl; 5-iso-propyl-phenyl; 2-CH3-phenyl; 4-CH3-phenyl; phenyl; 2-Cl-phenyl; 4-Cl-phenyl; 2-methoxy; 4-CH3CHCH-phenyl; 3,4CH3-phenyl; 2,4CH3-phenyl; 2,3CH3-phenyl; 2-iso-propyl; 5-CH3-phenyl; pyridyl; 1-imidazole; or 4-(1,2-benzisothiazole); and    further provided that if R5 is 3,5-dimethyl, or 4-methoxy-phenyl, then R1 is not 4-CH3, 6-CN-2-pyridyl; or thiophenecarboxamide; and pharmaceutical acceptable salts and complexes thereof; wherein said compound has an IC50≦10 μM using the Calcium Receptor Inhibitor Assay.
Maxine Gowen et al. examined the effect of a compound having a CaSR antagonistic action and called NPS-2143 on osteogenesis by orally administering NPS-2143 to OVX rat and measuring the concentration in blood and bone density, and reported the results [J. Clin. Invest., 105, 1595-1604 (2000)].
According to this publication, NPS-2143 significantly promotes release of PTH, but has no direct effect on osteoblast and osteoclast in vitro, as a result of which no bone increase or decrease was found. One of the reasons was considered to be the too long half-life of NPS-2143 in blood. When rat PTH (1-34) was administered to OVX rat at a dose of 5 μg/kg, the PTH concentration in blood shows a peak at about 175 pg/ml in 30 min, and restores its original level in 2 hr. When NPS-2143 was administered at a dose of 100 μmol/kg, PTH concentration kept increasing even after the PTH concentration in blood reached about 115 pg/ml in 30 min, and the concentration was about 140 pg/ml even after 4 hr [see J. Clin. Invest., 105, 1595-1604 (2000), p. 1598, FIG. 3].
At this time, the concentration in blood of NPS-2143 itself remained above 100 ng/ml even at 8 hr after administration and it was only after 24 hr when the concentration became not more than 10 ng/ml and could not be detected.
The reference of the above-mentioned Maxine Gowen et al. suggests that a calcium receptor antagonist having a too long half-life in blood brings about the same results as in sustained administration of PTH and teaches that an increase in the bone mass cannot be expected.
The present invention aims at providing a compound having a calcium receptor antagonistic action. The present invention also aims at providing a pharmaceutical composition comprising said compound, which is effective as an agent for the treatment of a disease showing abnormal calcium homeostasis, namely, osteoporosis, hypoparathyreosis, osteosarcoma, periodontal disease, bone fracture, steoarthrosis, chronic rheumatoid arthritis, Paget's disease, humoral hypercalcemia, autosomal dominant hypocalcemia and the like, particularly as a therapeutic agent for osteoporosis, which is capable of oral administration and intermittent administration. Moreover, the present invention aims at providing a synthetic intermediate for a compound having a calcium receptor antagonistic action.